Elsevier

Neuropharmacology

Volume 61, Issue 4, September 2011, Pages 849-856
Neuropharmacology

Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: Locomotor activity, drug discrimination and self-administration

https://doi.org/10.1016/j.neuropharm.2011.05.033Get rights and content

Abstract

Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1–3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1–3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1–1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse.

Highlights

► TBZ was 11-fold more potent inhibiting DAT than SERT. ► TBZ was 2.5-fold more potent inhibiting VMAT2 than DAT. ► TBZ at the lowest dose transiently increased methamphetamine self-administration. ► TBZ at high doses decreased methamphetamine and food-maintained responding. ► TBZ at high doses decreased locomotor activity and discriminative stimulus effects.

Introduction

Methamphetamine continues to be a prominent drug of abuse. According to the 2008 National Survey on Drug Use and Health, 850,000 Americans age 12 and older used methamphetamine at least once in the year prior to being surveyed, with past month users reaching 314,000 (Substance Abuse and Mental Health Services Administration, 2009). Between 1 and 2% of high school youth reported using methamphetamine at least once in the year prior to being surveyed (Johnston et al., 2009). As such, the discovery and development of pharmacotherapies for methamphetamine abuse remains critical, with current treatment strategies to promote abstinence relying mainly on behavioral interventions such as contingency management (Prendergast et al., 2006, Roll et al., 2006, Shoptaw et al., 2006). However, a pharmacological treatment for methamphetamine abuse would be highly beneficial to augment current treatment strategies, and thus, medication development remains an active research area.

Pharmacological actions of methamphetamine include: (1) augmentation of vesicular dopamine (DA) release from the vesicles and inhibition of the vesicular monoamine transporter-2 (VMAT2), resulting in decreased accumulation of DA into synaptic vesicles and increased cytosolic DA; (2) inhibition of monoamine oxidase (MAO), preventing the metabolism of cytosolic DA; and (3) reversal of the dopamine transporter (DAT), contributing to increased extracellular DA concentrations (Mantle et al., 1976, Sulzer et al., 1995, Brown et al., 2000, Brown et al., 2001, Fleckenstein et al., 2007). In concert, these actions of methamphetamine produce an increase in extracellular DA, which has been shown to be critical for its rewarding effects (Vollm et al., 2004).

Based on the mechanism of action of methamphetamine, VMAT2 has been identified as a potential pharmacological target for the treatment of methamphetamine abuse (Dwoskin and Crooks, 2002, Zheng et al., 2006). Inhibition of VMAT2 would be expected to redistribute DA from the vesicular to cytosolic pool, where it is metabolized by intracellular MAO, which may reduce the concentration of cytosolic DA available for methamphetamine-induced reverse transport of DAT, and thereby, attenuate the increase in extracellular DA mediating reward. Consistent with this possibility, heterozygous VMAT2 knockout mice display decreased amphetamine-evoked striatal DA release (Wang et al., 1997) and diminished amphetamine conditioned place preference (Takahashi et al., 1997). The VMAT2 inhibitor, lobeline, decreases both methamphetamine-evoked DA release and methamphetamine self-administration in outbred rats (Harrod et al., 2001, Harrod et al., 2003, Miller et al., 2001). However, lobeline also acts as a potent antagonist at nicotinic receptors, and less potently inhibits DAT function (Miller et al., 2000, Zheng et al., 2005, Wilhelm et al., 2008). Lobelane, a des-oxy lobeline analog, inhibits VMAT2 more potently and selectively than its parent compound (Miller et al., 2004, Zheng et al., 2005), and similarly decreases methamphetamine-evoked DA release and methamphetamine self-administration (Neugebauer et al., 2007, Nickell et al., 2010). The latter findings provide preclinical support for VMAT2 as a pharmacotherapeutic target for the treatment of methamphetamine abuse. Unfortunately, tolerance develops rapidly to the lobelane-induced decrease in methamphetamine self-administration (Neugebauer et al., 2007), revealing a pharmacological profile not suitable for clinical use.

Since the benzoquinolizine derivative, tetrabenazine (TBZ; Xenazine®) potently and reversibly binds to VMAT2 (Scherman et al., 1983, Erickson et al., 1996) and has been approved recently by the FDA for the treatment of chorea and other symptoms associated with Huntington’s disease (Yero and Rey, 2008), the current study assessed the preclinical effects of tetrabenazine on DAT, serotonin transporter (SERT) and VMAT2 function and on methamphetamine-induced behavioral effects, including hyperactivity, discriminative stimulus effects and self-administration. The aim was to evaluate its preclinical profile as a potential treatment for methamphetamine abuse.

Section snippets

Animals

Male Sprague-Dawley rats (250–275 g) were obtained from Harlan Industries (Indianapolis, IN, USA) and housed individually with ad libitum access to food (2018 Teklad Global 18% Protein Rodent Diet, Harlan; Madison, WI) and water in their home cage, except where noted, and were maintained in a temperature-controlled colony room on a 12:12-h light/dark cycle (lights on at 0700 h). Rats were handled and acclimated to the colony room for at least 1 week prior to the start of the behavioral

Effect of TBZ on [3H]DA and [3H]5-HT uptake into synaptosomes

Inhibition of [3H]DA and [3H]5-HT uptake into synaptosomes by TBZ is illustrated in Fig. 1A. TBZ inhibited DAT and SERT function with Ki values of 0.18 μM and 1.97 μM, respectively.

Effect of TBZ on [3H]DA uptake into synaptic vesicles

Inhibition of [3H]DA uptake into synaptic vesicles by TBZ is illustrated in Fig. 1A. TBZ inhibited [3H]DA uptake with a Ki value of 0.07 μM. To elucidate the mechanism of TBZ-mediated inhibition of VMAT2, kinetic analyses were performed (Fig. 1B). TBZ increased Km compared to control (Km = 0.35 and 0.14 μM,

Discussion

The current study sought to evaluate TBZ, which has been approved for the treatment of chorea associated with Huntington’s disease, as a potential treatment for methamphetamine abuse. Analogs of TBZ have been used extensively as radioligand probes for VMAT2 in neurological studies evaluating neurodegeneration due to its specific high affinity binding to this presynaptic protein (Frey et al., 1996, Bohnen et al., 2000). Also, TBZ has been reported to potently inhibit monoamine transport at VMAT2

Disclosure statement

The University of Kentucky holds patents on lobeline, lobelane, and novel analogs of these compounds. A potential royalty stream to Dwoskin may occur consistent with University of Kentucky policy.

Acknowledgments

This research was supported by NIDA grants R01 DA13519 and T32 DA016176.

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